The majority of cases have a mutation in the paired box gene (PAX6) complex, or at least include this locus when chromosomal aberrations such as deletions are present in the region (11p13). This complex (containing at least 9 genes) is multifunctional and important to the tissue regulation of numerous developmental genes. PAX6 mutations, encoding a highly conserved transcription regulator, generally cause hypoplasia of the iris and foveal hypoplasia but are also important in CNS development. It has been suggested that PAX6 gene dysfunction may be the only gene defect associated with aniridia. More than 300 specific mutations, most causing premature truncation of the polypeptide, have been identified.
AN1 results from mutations in the PAX6 gene. Two additional forms of aniridia have been reported in which functional alterations in genes that modulate the expression of PAX6 are responsible: AN2 (617141) with mutations in ELP4 and AN3 (617142) with mutations in TRIM44. Both ELP4 and TRIM44 are regulators of the PAX6 transcription gene.
Associated abnormalities may be due to a second mutation in the WT1 gene in WAGR (194072) syndrome, a deletion syndrome involving both WT1 and PAX6 genes at 11p13. The WAGRO syndrome (612469) is caused by a contiguous deletion in chromosome 11 (11p12-p13) involving three genes: WT1, PAX6, and BDNF. All types are likely inherited as autosomal dominant disorders although nearly one-third of cases occur sporadically.
Mutations in PAX6 associated with aniridia can cause other anterior chamber malformations such as Peters anomaly (604229).
Gillespie syndrome (206700 ) is an allelic disorder with neurological abnormalities including cerebellar ataxia and mental retardation.